JPH0670026B2 - 1,4-disubstituted piperazine derivative, pharmaceutical composition containing the same and method for producing the same - Google Patents

Abstract

The invention relates to novel 1,4-disubstituted piperazine derivatives of the general formula (I), pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, pharmaceutical compositions containing them and a process for their preparation. In the general formula (I) <IMAGE> (I) R1, R2, R3 and R4 are the same or different and stand for hydrogen or halogen or a trihalomethyl, lower alkyl, lower alkoxy, nitro, hydroxyl, aralkyloxy or an 1-(2-propenyl-4-piperazinyl) group; R5 stands for hydrogen or a C1-4 alkyl group; R6 represents a C3-6 alkyl, alkenyl, alkynyl group or a <IMAGE> group, wherein R7 means a C2-5 alkyl, alkenyl or alkinyl group; and is 2 or 3, with the provisos that: R6 is different from isopropyl, n-butyl and isobutyl group when R2, R3, R4 and R5 stand for hydrogen, R1 means 2-chloro and n is 2; R6 is different from isopropyl group when R2, R3, R4 and R5 stand for hydrogen, R1 means 2-chloro and n is 2; or when R2, R3, R4 and R5 stand for hydrogen, R1 means 2-methyl group and n is 2; and R6 is different from propionyl group when R1, R2, R3, R4 and R5 are hydrogen and n means 2. The compounds of the general formula (I) are therapeutically useful for the treatment of diseases arising from a hypofunction of the dopaminergic system.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention provides the following general formula (I): In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other and are a hydrogen atom, halogen, trihalomethyl group, lower alkyl group, lower alkoxy group, nitro group, hydroxyl group, phenyl C _1-4 alkyloxy groups or 1- (2
-Propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl group) , N is an integer of 2 or 3, and relates to a novel diphenylmethoxyalkylpiperazine derivative represented by: and a pharmacologically usable acid addition salt thereof, a quaternary ammonium salt thereof, and a pharmaceutical composition containing the same.

Furthermore, the present invention provides a novel compound of the above general formula (I),
It relates to a method for producing the acid addition salt and the quaternary ammonium salt.

(Prior Art) Regarding the production of known compounds of this type, the following documents can be mentioned.

H.G.Morren: Industrial Chemistry (HGMorren: Ind Chim.) Belge 22 , 409 (1957) (CA
52, 12873i); Belgian Patent Specification No. 551,032 and No. 549,420 (CA 53, 20101f and CA 54, 12169a); French patent specification No. 2,276,824 (CA, 85, 160163p) .

According to pharmacological studies, these compounds show a large ulcer inhibitory action and a weak antihistamine effect, and no other pharmacological action is shown. The compounds described in the above French patent specifications are said to have a cough suppressing effect.

(Detailed Description of the Invention) The novel compound represented by the above general formula (I) provided by the present invention exhibits cooperative and selective dopaminergic activity on the central nervous system, and therefore, degeneration or function of the dopamine system. It has been found by the present inventor to be effective against diseases caused by depression, such as depression, Parkinson's disease, various neuroendocrine diseases, aging and apathy.

That is, the dopaminergic activity of the compound of the present invention was confirmed by an in vitro test and a living animal test. In the test of in vivo activity, the compound 1-methyl-4-
The protective function of phenyl-1,2,3,6-tetrahydropyridine (MPTP) against neurotoxic effects was also investigated.

In 1979, it was reported that the above MPTP caused a decrease in the function of the dopamine system in humans and monkeys [GC Davis et al .: Psychiatrial Research (GCDa
vis et al:. Psychiat.Res) 1 , 249 (1979); R.
S. Burns other: Puroshidengusu of National Academy of Sciences (USA), 80, 4546
(1983)]; This MPTP is known to have a damaging effect on the selective dopamine system in mice (H. Harman et al .:
European Journal of Pharmacology (H. Hallman et al Eur.J.Pharmacol.) 97 , 133 (198
. 4); e-Pireburaddo other: Neuro-Pharmacology (E.Pileblad et al: Neuropharmacol) 24 , 689 (198
6)].

The process obtained in experimental animals for the selective dopaminergic damage by MPTP appears to be common in human dopaminergic degeneration or hypofunction.
Therefore, it provides a suitable model for investigating compounds useful in the treatment of diseases associated with the pathological functions of the dopamine system [AJ Bradbury et al: The Lancet. Lancet) 1985 ,
1444; H. Pltuntech et al .: Life Science (H. Przuntek et al: Life Sci. 37 , 1195 (1985)].

In these experiments, male CFY mice (LATI, Gdl
L, Hungary), with a body weight of 20 to 25 g. The compound to be tested was homogenized in a 1% Tween 80 solution and then administered to test animals 1 mmol / kg (route indicated in table) 1 hour before MPTP administration.

MPTP was newly dissolved in physiological saline and this was added to mice.
It was subcutaneously administered at a dose of mg / kg. 72 to 96 hours after the administration of MPTP, the mice were killed by decapitation, the brains were immediately taken out, cooled with ice-cold physiological saline solution, and the striatum was cut out and frozen in dry ice.

After weighing the frozen tissue, 0.5% Ma ₂ S ₂ O ₅ ,
With 0.25% Na ₂ EDTA and 100 ng M-methyldopamine, an internal standard for the determination of catecholamines.
It was put into 1 ml of a 4N perchloric acid solution, and dispersed and homogenized using an Ultra-Turrax apparatus.

The homogenate was centrifuged at 20,000 G for 10 minutes at 4 ° C., and 0.8 ml of the supernatant was taken out. Furthermore, after adding 20 mg of activated alumina, the pH of this solution was adjusted to 8 by adding a 0.5 M Tris solution, and this was shaken for 20 minutes.

As a result, alumina was deposited. The supernatant was removed by suction and washed 3 times with 5 ml of distilled water. Catecholamines adsorbed on alumina were eluted with 1 ml of 0.05N perchloric acid.

An analytical measurement of dopamine was carried out from a part of this eluate by high pressure liquid chromatography using an electrochemical test method (Labor MIM Oe-320 pump, 4 × 150 mm Nuc.
leosil 5C-18 analytical column, 4 × 20mm Nucleosil 5C-1
8 Auxiliary column; glass-like carbon working electrode and Ag / AgCl
Electrochemical analyzer with ₂ reference electrodes; Eltron Potentiostat LKB2110 2-channel recorder; 600 mV oxidation potential, 0.1 mM NaH ₂ PO ₄ , 1 mM NaEDTA as driving phase, and 1 mM octane sulfone with 8.5% acetonitrile. Acid; flow rate 1 ml / min).

The method described above was able to reduce striatal dopamine levels by 50-60%. The protective capacity against MPTP-induced dopamine reduction was calculated by the following formula.

As a reference drug, trihexyphenylidyl chloride (α
-Cyclohexyl-α-phenyl-1-piperidine propanol chloride) was used at a dose of 10 mg / kg (<0.1 mmol / kg). Mice died at higher doses. The results are shown in the table. The following abbreviations are used in the table.

MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine chloride DA: Dopamine n: Number of animals ip: Intraperitoneal administration op: Oral administration (Compound) No. 1… 1- [2- [ Bis (4-fluorophenyl) methoxy] ethyl] -4- (2-propenyl) -piperazine No. 2 ... 2- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4-propylpiperazine No. 3 1- [2-[(4-fluorophenyl) phenylmethoxy] ethyl] -4- (2-propenyl) piperazine No. 4 ... 1- [2-[(4-chlorophenyl) -4-fluorophenyl) methoxy] -Ethyl] -4- (2-propenyl) piperazine No. 5 ... 1- [2-[(4-Bromophenyl) -4-fluorophenyl) methoxy] -ethyl] -4- (2-propenyl) piperazine No. 6 ... 1- [2- [bis (4 Chlorophenyl) methoxy] ethyl] -4- (2-propenylpiperazine No. 7 ... 1- [2-[(3,4-dichlorophenyl) -phenylmethoxy] ethyl] -4- (2-propenyl) -piperazine No. 8 1- [2-[(4-chlorophenyl)-(4-fluorophenyl) methoxy] -ethyl] -4-propylpiperazine No. 9 ... 1- [2 [bis (4-fluorophenyl) methoxy] -ethyl] -4-Butylpiperazine No. 10 ... 1- [2- [1-bis (4-fluorophenyl) ethoxy] ethyl] -4- (2-propenyl) piperazine No. 11 ... 1- [2- [1- Bis (4-fluorophenyl) methoxy] ethyl] -4- (1-oxohexyl)
Piperazine No. 12 ... 1- [2- [1-bis (4-fluorophenyl) methoxy] ethyl] -4- (2-propynylpiperazine) No. 13 ... 1- [2- [1-bis (4-fluoro Phenyl) methoxy] ethyl] -4- (2-methyl-2-propenyl) piperazine No. 14 ... 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4- (1-oxopropyl) piperazine No. 15 ... 1- [2- [3,4-dichlorophenyl) -phenylmethoxy) ethyl] -4-butylpiperazine No. 16 ... 1- [2-[(4-chlorophenyl)-(4-
Fluorophenyl) methoxy] -ethyl] -4-butylpiperazine No. 17 ... 1- [2 [bis (4-fluorophenyl) methoxy] -ethyl] -4-hexylpiperazine The above compounds No. 11 and No. 14 are The monohydrochloride salt and the other compound is the dihydrochloride salt.

As is evident from the data in this table, when administered orally or intraperitoneally to animals prior to treatment with MPTP, compounds of general formula (I) significantly or completely suppress the neurotoxic dopamine deficient effect of MPTP. be able to. Furthermore, the compound of general formula (I) is advantageous in that it has low toxicity.

Therefore, the novel compound of the present invention shows an effective therapeutic effect on diseases in which dopamine function decline is caused by degeneration of the dopamine system and other causes.

The compound of general formula (I) according to the present invention is produced as follows.

(A) Compound of the following general formula (II): [Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as above, and Y is OM
A group [where M is an alkali metal or MgHlg (where Hlg is a halogen)], and Y is a hydroxyl group], represented by the following general formula (III) compound: (In the formula, R ₆ and n are the same as above, X is halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group when Y is an OM group, and halogen, a hydroxyl group, an alkylsulfonyloxy group when Y is a hydroxyl group. Or an arylsulfonyloxy group), or (b) a compound of the following general formula (IV): (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Hlg are the same as above) and is represented by the following general formula (V): [Wherein R ₆ and n are the same as above, Y is a hydroxyl group or an OM ′ group (M ′ is an alkali metal)], or (c) a compound of the following general formula (VI): (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as above, Z is a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group), and the piperazine derivative of the following general formula (VII): (Wherein R ₆ is the same as above), or (d) a compound of the following general formula (VIII): (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as above),
Compound of the following general formula (IX): ZR ₆ (IX) (wherein Z and R ₆ are the same as above), or (e) compound of the general formula (I) (provided that R ₁ and R ₂ , R ₃ , R ₄ ,
R ₅ and n are as described above, R ₆ is partially or completely reduced from a C _3-6 alkynyl group to give a compound of the general formula (I) (wherein R ₆ is C
_{3 to 6} alkenyl group or alkyl group, R ₁ , R ₂ , R ₃ , R ₄ ,
R ₅ and n are the same as the above), or (f) an acid amide of the following general formula (X): (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as above.
₆ is a C _3-6 alkyl group, an alkenyl group or an alkynyl group), and, if desired, the compound obtained by the above-mentioned methods (a) to (i) is added to an acid addition salt with an organic acid or an inorganic acid. To a quaternary ammonium salt with a quaternizing agent, and if desired, the acid addition salt or quaternary ammonium salt is converted to the corresponding free base. It is prepared by converting the base into its acid addition salt or quaternary ammonium salt.

The compounds of general formula (I) may contain one or more asymmetric carbon atoms and are therefore capable of forming various stereoisomers.

Further, the compound of the general formula (I) may be a base, an acid addition salt, a quaternary ammonium salt, a racemate, an optical isomer and a mixture thereof, a solvate (for example, a hydrate) or the like.

Starting materials are known and can be obtained by methods known in the known literature.

The benzhydrol of the general formula (II) (wherein Y is a hydroxyl group or an OMGHlg group (Hlg means halogen)) can be obtained, for example, by reacting a suitable carbonyl compound with a Grignard reagent [MS・ Carlass et al .: Grignard reaction of non-metallic substances (MSKharasch et al: G
rignard Reaction of Nonmetallic Substances) Ed.Pre
ntice-Hall Inc., pp. 138-143 (1954)].

The alcohol of the general formula (V) is obtained by alkylating the mono-substituted piperazine of the general formula (VII) with a haloalkanol of the general formula, Hlg- (CH ₂ ) _n- OH (where n and Hlg are as described above). Can be manufactured.

The halogenated derivative of the general formula (III) can be produced by reacting the alcohol of the general formula (V) with thionyl chloride. [O.Hromatka e
t al): Monatshefte 87 , 701 (1956)].

Alkoxides of general formulas (II) and (V) (provided that Y
The OM 'group (M' is an alkali metal) can be obtained by reacting a suitable alcohol with an alkali metal, an alkali metal hydride or an alkali metal amide [Houben-Weil: Mesoden del Organischen.・ Chemie (Houben-Weyl: Methoden der Organische
n Cheime) VI / 2,6-34 (1963)].

For the preparation of compounds of general formula (IV)
Hamlin et al .: Journal of American Chemical Society (KEHamlin et al: J.Am.Chem.Soc.) 7
1 , 2731 (1949); or Earl Baltree et al .: Journal of Organic Chemistry (R. Baltzly et.
al: J.Org.Chem.) 14,775 (1949).

The ether compound of the general formula (VI) can be produced by using the method of Sugasawa described in the literature, Organic Synthesis (Org.Synth.) 33 , 11 (1953).

The monosubstituted piperazine derivatives of general formulas (VII) and (VIII) can be prepared by the method of Kiichi Fujii [J.Pharm.Soc.Japan] 74 , 1049 (1954)],
Or the method of H. W. Schiwald [Journal of Organic Chemistry (J.Org.Chem.) 13 ,
134 (1948)] or the method of T. Irikura [J. of Medical Chemistry (J.
Med.Chem.) 11,801 (1968)], or the method of Belgian patent specification No. 549,420.

The starting material of the general formula (X) is the alkoxide of the general formula (II): (Wherein R ₆ , n and Hlg are as described above) can be obtained by reacting with a compound under the same conditions as in the method of (a) above.

Compounds of general formula (XI) are described in US Pat. No. 3,041,341
No. (CA 57 , 13778d).

According to the method (a) of the present invention, the compound of the general formula (II) (wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as above, Y is
OMgHlg group (Hlg is a halogen)), a piperazine derivative of the general formula (III) (wherein R ₆ and n are the same as above, X is a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group) and an anhydrous organic solvent (reaction (Which is inert under the conditions).

In this case, as the reactive derivative of the compound of the general formula (III), its mesylate or tosylate, preferably chloride or bromide is used.

This reaction is preferably carried out under an inert gas atmosphere such as nitrogen or argon.

Useful solvents in this case are aliphatic or cycloaliphatic ethers such as di (n-butyl) ether, tetrahydrofuran, dioxane; aliphatic or aromatic hydrocarbons such as n-hexane, lycloine, benzene, toluene, xylene; Dimethyl sulfoxide, hexamethylphosphoramide, and mixtures of these solvents are used.

In the compound of the general formula (II), Y is a hydroxyl group,
If a reactive derivative of the compound of I) is used, the reaction is preferably carried out in the presence of an inorganic or tertiary organic base effective to bind the acid released during the reaction.

However, the compound of general formula (III) may be used in excess as the acid binder. This reaction can be carried out in an inert organic solvent, but it may also be carried out without a solvent.

When both X and Y are hydroxyl groups, the condensation reaction is
It is carried out in the presence of organic or inorganic acids, or salts thereof commonly used to promote ether formation, in air or under reduced pressure, and the water formed is removed by azeotropic distillation.

Useful solvents in this case are aromatic or aliphatic hydrocarbons,
For example, n-heptane, toluene, xylene; aliphatic ether or alicyclic ether such as di (n-butyl) ether, dioxane and the like.

According to the method (b) of the present invention, a halogenated benzhydryl of the general formula (IX), preferably chloride or bromide,
The piperazine derivative of the general formula (V) is reacted under the same conditions as in the above method (a).

After the reaction is complete, the product is separated. That is, the reaction mixture is poured into water and the products are separated by solvent extraction. The organic phase is washed with water until the reaction is complete, then dried and evaporated. The crude product obtained is purified, for example by chromatography or recrystallization.

According to the method (c) of the present invention, a reactive derivative of the compound of the general formula (VI), preferably a mesylation product, a tosylation product,
The bromide and chloride are converted to 1-alkyl- of the general formula (VII),
It is reacted with a 1-alkenyl- or 1-alkynyl-piperazine derivative (provided that R ₆ is the same as above). This reaction is
It is carried out in an organic solvent in the presence of a base effective to bind the acid released during the reaction.

Suitable solvents for this reaction include hydrocarbons such as ligroin, benzene, toluene, xylene, halogenated hydrocarbons such as chloroform, alcohols such as ethanol, esters such as ethyl acetate, acid amides such as dimethylformamide, Acetone, ketones such as methyl isobutyl ketone, or a mixture thereof can be used.

As the acid binder, inorganic or tertiary organic bases such as carbonates and hydroxides of alkali metals, triethylamine and pyridine, as well as the piperazine derivative of the general formula (VII) can be used in excess.

This excess piperazine derivative can also be used as a solvent.

This reaction is carried out at a temperature in the range of 20 ° C. to the boiling point of the solvent, optionally using a catalyst. An example of this catalyst is
It is an alkali metal iodide.

In the method (d) of the present invention, 1-benzhydryloxyalkylpiperazine is added to a compound of the general formula (IX):
The reaction is preferably carried out under the same conditions as in the above method (c).

According to the method (e) of the present invention, the novel compound of the general formula (I) (provided that R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as those described above for R ₆
Is a _C3-6 alkynyl group) optionally another novel compound of general formula (I), i.e. a corresponding alkenyl derivative, via partial or total reduction of the triple bond,
Alternatively, it is converted into an alkyl derivative.

When this reduction is continued, for example in the presence of a catalyst effective for the partial saturation of triple bonds, up to the withdrawal of 1 mol of hydrogen, new compounds of the general formula (I) (R ₆ is an alkenyl group) are obtained. To be

A useful catalyst for this is, for example, the Raney nickel catalyst, which is inhibited with zinc acetate and is used in the presence of piperidine. In addition, in the presence of quinoline, Lindola catalyst: (P
d (CaCO ₃ ) PbO) may be used.

When reduction is carried out until the triple bond is completely saturated,
Compounds of general formula (I) (wherein R ₆ is an alkyl group)
Is obtained.

This reduction is preferably carried out by catalytic hydrogenation. Suitable catalysts for this hydrogenation are metals such as ruthenium, palladium, platinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum, tungsten, or oxides or sulfides of these metals. This catalytic hydrogenation is carried out using a catalyst that is previously deposited on the surface of the carrier. In this case, useful carriers include
Carbon, silicon dioxide, aluminum oxide, carbonates and sulfates of alkaline earth metals.

This reduction is carried out by hydrogenation in the presence of a catalyst such as palladium, platinum or Raney nickel in a solvent inert to the reaction. Useful solvents in this case are, for example, lower aliphatic alcohols, ethers, esters, aliphatic hydrocarbons, aromatic hydrocarbons or mixtures of these solvents. This hydrogenation is performed under atmospheric pressure or under pressure at a temperature of 20 ° C.
To the boiling point of the reaction mixture.

The reduction is continued until a calculated amount of hydrogen has been taken up, after which the catalyst is filtered and the filtrate evaporated,
The resulting product is purified by distillation or recrystallization.

In the method (f) of the present invention, the acid amide of the general formula (X) (provided that R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and n are the same as above) is reduced by the following method. To do.

This reduction reaction is carried out under an inert gas atmosphere such as nitrogen or argon in an inert organic solvent (for example, an aliphatic or alicyclic ether such as ethyl ether, tetrahydrofuran, or a mixture thereof, for example, It is carried out with lithium aluminum hydride, the complex thus formed then being hydrolyzed.

The compound of the above general formula (I) can be converted into a pharmacologically usable acid addition salt or quaternary ammonium salt by a known method, if desired. That is, in the production of acid addition salts, inorganic or organic acids, such as hydrogen chloride,
Hydrogen halide such as hydrogen bromide; sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, Benzoic acid, cinnamic acid, aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutamic acid; alkanesulfonic acids such as methanesulfonic acid and arenesulfonic acids such as p-toluenesulfonic acid can be used.

The acid addition salt is prepared by adding a suitable acid to a solution of the compound of general formula (I) dissolved in an inert solvent, for example, an ethanol solution,
The salt obtained is then precipitated by addition of a water-immiscible organic solvent, for example ethyl ether.

The quaternary ammonium salt is produced using a lower alkyl, a lower alkenyl, a lower benzyl halide, or an alkyl sulfate. This quaternization reaction is carried out in an organic solvent, preferably acetone, acetonitrile, ethanol or a mixture thereof at room temperature to the boiling point of the solvent.

The quaternary salt thus formed is separated by filtration and, if desired, purified by recrystallization.

The compounds of the present invention can also be converted into various forms of pharmaceutical compositions. These pharmaceutical compositions can be administered orally, enterally or parenterally.

For oral administration, the pharmaceutical composition can be formulated as tablets, dragees and capsules. Lactose, starch or the like can be used as an excipient in the production of a drug for oral administration. Suitable binders or granulating agents are gelatin, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, starch gum. As the dispersant, in addition to potato starch or microcrystalline cellulose, ultra amylopectin or formaldehyde-casein can be used. Further, colloidal silicic acid, stearin, calcium stearate, magnesium stearate and the like can be used as an anti-adhesion / lubrication agent.

The tablets can be produced, for example, by wet granulation and then compression. A mixture containing an active ingredient, an excipient, and optionally a dispersant, together with an aqueous solution of a binder, an ethanol solution or a water / ethanol solution is granulated by a suitable granulator, and then the granules are granulated. To dry.
Next, the dry granules are mixed with a dispersant and a slipping / anti-adhesive agent, and the mixture is compression molded into tablets. The tablet may be provided with a dividing groove.

It is also possible to produce a tablet by directly compressing a mixture containing an active ingredient and necessary additives. If desired, tablets may be added to sugar, cellulose derivatives (methyl cellulose or ethyl cellulose derivatives (methyl cellulose or ethyl cellulose, or sodium carboxymethyl cellulose), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, fragrances, iron oxide pigments, and other pharmaceutical industries. It is also possible to convert to sugar-coated tablets by using the additives generally used in.

The production of capsules is carried out by filling the capsules with the active ingredients together with additives.

For enteral administration, the pharmaceutical composition is used in the form of suppositories. In addition to the active ingredient, this suppository contains a so-called suppository fat as a base substance for shaping. In this case, as the excipient, vegetable fat such as hydrogenated vegetable oil, C
_{A 12-18} fatty acid triglyceride is used, preferably the excipient commercially available as "Witepsol" (TM). The active ingredient is uniformly dispersed in the molten excipient material and then shaped to give a suppository.

For parenteral administration, the pharmaceutical composition is prepared as a solution for injection. In the preparation of this injectable solution, the active ingredient is distilled water or various organic solvents (eg glycol ether), and optionally a solubilizing agent (polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan mono). Ole art (Tween 60),
Alternatively, it is dissolved in the presence of polyoxyethylene sorbitan monostearate (Tween 80).

Injectable solutions also include various additives, such as preservatives (e.g., benzyl alcohol, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate,
Benzalkonium chloride, phenylmercuric borate), antioxidants (eg ascorbic acid, tocophenol, sodium pyrosulfate), and optionally complex-forming agents (eg ethylenediaminetetraacetate) for binding to metal roots, for pH adjustment Buffering agents, local anesthetics (eg lidocaine) may be added.

The injectable solution containing the active ingredient of the present invention is filtered before being filled in an ampoule, and sterilized after filling.

The daily dose depends on the condition of the patient and the medical condition to be treated, but in the case of adults, it is generally 5 by oral administration.
To 200 mg.

The present invention also relates to a method for treating a disease caused by a decrease in dopamine level, that is, a disease caused by a decrease in the function of the dopamine system, which method is represented by the general formula (I) It comprises administering to a patient in need of treatment a therapeutically effective amount of a substituted piperazine derivative, or a pharmaceutically acceptable acid addition salt thereof, or a quaternary ammonium salt thereof.

(Examples) Hereinafter, examples of the present invention will be described in detail.

Example 1 1- [2- [bis (4-fluorophenyl) methoxy]
Preparation of ethyl] -4- (2-propenyl) piperazine dihydrochloride 2.4 g 50% sodium hydride (oil dispersion) and 4,4 '
-11.0 g of difluorobenzhydrid, 60 m of anhydrous toluene
The suspension containing what was dissolved in 1 was refluxed for 15 minutes in an argon atmosphere. Next, a solution prepared by dissolving 9.4 g of 1- (2-chloroethyl) -4- (2-propenyl) piperazine in 70 ml of anhydrous toluene was added dropwise thereto. The resulting mixed liquid was refluxed for another 2 hours and then cooled, and 40 ml of water was added thereto. Then, the organic layer is separated,
It was washed with water to remove chloride completely, dried with anhydrous sodium sulfate and then evaporated under reduced pressure.

The obtained residue was purified using a Kieselgel column using a benzene / methanol mixture as an eluent. Appropriate fractions were evaporated, the residue was dissolved in anhydrous isopropanol and hydrogen chloride ether solution was added thereto to precipitate the desired salt. The melting point of this dihydrochloride is 18
The temperature was 9 to 191 ° C.

Elemental analysis: as _{C 22 H 26 F 2 N 2} O ( base): Calculated (%): C 70.94; H 7.04; F 10.20; N 7.52 Found (%): C 70.77; H7.11 ; F 10.40; N 7.63 Example 2 Preparation of 1- [2-[(4-chlorophenyl)-(4-fluorophenyl) methoxy) ethyl] -4- (2-propenyl) piperazine dihydrochloride 2-[(4-chlorophenyl)-( 4-Fluorophenyl) methoxy) ethyl chloride 18.0 g, 1-allylpiperazine 6.3 g, anhydrous potassium carbonate and potassium iodide
A mixed solution of 0.83 g dissolved in 170 ml of methyl isobutyl ketone was refluxed for 15 hours while stirring. Then, after it was cooled, the reaction mixture was evaporated under reduced pressure. After adding water to this reaction mixture, extraction was performed using benzene. The organic layer of the obtained extract was washed with water, dried over anhydrous sodium sulfate, and after evaporation, the residue was taken up in anhydrous ether. This ethanol solution was treated with a hydrogen chloride ethanol solution, and the precipitated salt was filtered and dried to obtain the desired dihydrochloride. The melting point of this dihydrochloride was 199-200 ° C.

Elemental analysis: as C ₂₂ H ₂₆ ClFN ₂ O (base): Calculated value (%): C 67.94; H 6.74; Cl 9.12; N 7.20; F 4.89 Experimental value (%): C 68.10; H 6.53; Cl 9.30; N 7.08; F 5.10 The following compounds were made using the same method as in the above example.

(A) 1- [2-[(2-chlorophenyl)-(4-fluorophenyl) -methoxy] ethyl] -4-propylpiperazine dihydrochloride (melting point: 213-214 ° C)
Is 1-chloro-2-[(2-hydroxyethoxy)-
(4-Fluorophenyl) -methyl] benzene Obtained by reacting methanesulfonate with 1-propylpiperazine.

Elemental analysis: as C ₂₂ H ₂₈ ClFN ₂ O (base): Calculated (%): C 67.59; H 7.22; Cl 9.07; F 4.86; N 7.17 Found (%): C 67.66; H 7.38; Cl 9.24; F 5.03; N 7.40 (b) 1- [3- (diphenylmethoxy) propyl]-
4-Propylpiperazine (Melting point: 185-188 ℃ / 0.01Hgmm)
Was obtained by reacting 1-[(3-hydroxypropoxy) phenylmethyl] benzene p-toluenesulfonate with 1-propylpiperazine.

Elemental analysis: As C ₂₉ H ₃₂ N ₂ O (base): Calculated value (%): C 78.36; H 9.15; N 7.95 Experimental value (%): C 78.41; H 9.30; N 8.07 (c) 1- [2 -[3-Nitro-4- [4- (2-propenyl) piperazin-1-yl-phenyl] -phenylmethoxy] ethyl] -4- (2-propenyl) piperazine tetramaleate (melting point: 109-112 ° C) Is 2-
Obtained by reacting [(4-chloro-3-nitrophenyl) -phenylmethoxy] ethyl chloride with 1- (2-propenyl) piperazine.

Elemental analysis: As C ₂₉ H ₃₉ N ₅ O (base): Calculated value (%): C 68.88; H 7.77; N 13.85 Experimental value (%): C 68.67; H 7.84; N 13.97 (d) 1- [2 -[(4-Chlorophenyl)-(4-fluorophenyl) methoxy] ethyl] -4- (2-propynyl) piperazine dihydrochloride (mp 186-188)
C) was obtained by reacting 2-[(4-chlorophenyl)-(4-fluorophenyl) ethoxy] ethyl chloride with 1- (2-propenyl) piperazine.

Elemental analysis: As C ₂₂ H ₂₄ ClFN ₂ O (base): Calculated value (%): C 68.29; H 6.25; Cl 9.16; F 4.91; N 7.24 Experimental value (%): C 68.47; H 6.38; Cl 9.00; F 4.77; N 7.32 (e) 1- [2-[(3,4-dichlorophenyl) phenylmethoxy] -ethyl] -4- (2-propynyl) piperazine dihydrochloride (melting point: 201-203 ° C) is brominated. Obtained by reacting 2-[(3,4-dichlorophenyl) phenylmethoxy] ethyl with 1- (2-propynyl) piperazine.

Elemental analysis: as _{C 22 H 24 Cl 2 N 2} O ( base): Calculated (%): C 65.71; H 6.00; Cl 17.58; N 6.95 Found (%): C 65.60; H 6.11; Cl 17.33; N 7.13 (f) 1- [2-[(4-Bromophenyl)-(4-fluorophenyl) methoxy] -ethyl] -4- (2-propynyl) piperazine dihydrochloride (mp 179-1
81 ° C.) is 2-[(4-bromophenyl)-(4-
Fluorophenyl) methoxy] ethyl], 1- (2-
Obtained by reacting with propynyl) piperazine.

Elemental analysis: C ₂₂ H ₂₄ BrFN ₂ O as (basic): Calculated (%): C 61.26; H 5.61; Br 18.53; F 4.40; N 6.49 Found (%): C 61.17; H 5.83; Br 18.44; F 4.61; N 6.40 (g) 1 [2-[(4-fluorophenyl) -phenylmethoxy] ethyl] -4- (2-propynyl) piperazine dihydrochloride (melting point: 186-187 ° C) is 2- Obtained by reacting [(4-fluorophenyl) -phenylmethoxy] ethyl chloride with 1- (2-propynyl) piperazine.

Elemental analysis: As C ₂₂ H ₂₅ FN ₂ O (base): Calculated value (%): C 74.97; H 7.15; F 5.39; N 7.95 Experimental value (%): C 75.21; H 7.34; F 5.55; N 7.79 ( h) 1- [2- [bis (4-chlorophenyl) methoxy] ethyl] -4- (2-propynyl) piperazine dihydrochloride (melting point: 194-196 ° C) is 2- [bis (4-chlorophenyl) methoxy] Obtained by reacting ethyl tosylate with 1- (2-propynyl) piperazine.

Elemental analysis: as C ₂₂ H ₂₄ Cl ₂ O (base): calculated (%); C 65.51; H 6.00; Cl 17.58; N 6.95; experimental (%); C 65.69; H 5.87; Cl 17.45; N 6.84 Example 3 1- [2- [1- (2,5-dimethylphenyl) -1-phenylpropoxy] ethyl] -4- (2-propenyl)
Production of piperazine dihydrogen fumarate 1- [2- [1- (2,5-dimethylphenyl) -1-phenylpropoxy] ethyl] piperazine 10.6g, anhydrous potassium carbonate powder 4.6g dissolved in anhydrous benzene 90ml A solution prepared by dissolving 3.6 g of allyl bromide in 10 ml of benzene was added dropwise to the liquid while slowly refluxing. The reaction mixture was then boiled for another hour. After cooling it, water was added, then the organic layer was separated, washed with water until neutral, dried with anhydrous sodium sulfate and evaporated under reduced pressure.

An absolute ethanol solution of this evaporation residue was treated with a fumaric acid ethanol solution, and the solid precipitate was recrystallized with methanol to obtain the desired dihydrogen fumarate (melting point: 2
02-204 ° C) was obtained.

Elemental analysis: As C ₂₆ H ₃₆ N ₂ O (base): Calculated value (%); C 79.54; H 9.24; N 7.14; Experimental value (%); C 79.31; H 9.28; N 7.30. Example 4 1- Preparation of [2- [bis (4-fluorophenyl) -methoxy] ethyl] -4-hexylpiperazine dihydrochloride 2.3 g of lithium aluminum hydrogen was dissolved in 60 ml of anhydrous ether, and 1- [2- [bis (4 A solution of 21.5 g of -fluorophenyl) methoxy] ethyl] -4- (1-oxohexyl) piperazine dissolved in 100 ml of anhydrous ether was added dropwise under stirring in a nitrogen atmosphere. The reaction mixture was refluxed for an additional 1 hour, then cooled to 0 ° C. and further decomposed by adding an aqueous sodium hydroxide solution. The resulting precipitate was filtered and the ether washed. Next, this ether washing liquid is combined and washed with water,
It was dried over anhydrous magnesium sulphate and evaporated.

The residue was dissolved in ethanol, and hydrogen chloride ethanol solution was added to precipitate the desired salt. The melting point of the obtained product was 212 to 213 ° C.

Elemental analysis: C ₂₅ H ₃₄ F ₂ N ₂ O (base): Calculated value (%); C 72.08; H 8.23; F 9.12; N 6.73; Experimental value (%); C 72.20; H 8.28; F 9.18; N 6.70. Example 5 Preparation of 1- [2- [bis (4-fluorophenyl) -methoxy] ethyl] -4- (1-oxopropyl) piperazine dihydrochloride 2.3 g of propionyl chloride and 10 ml of 1,2-dichloroethane Dissolved in 80 ml of 1,2-dichloroethane 1- [2-
[Bis (4-fluorophenyl) methoxy] -ethyl]
A solution of 8.3 g of piperazine and 4.2 ml of triethylamine was added dropwise, and the mixture was stirred for another 30 minutes.

Next, water was added to the reaction mixture, the organic layer was separated, washed with water, dried using anhydrous magnesium sulfate, and further evaporated under reduced pressure.

The obtained residue was dissolved in ethanol, a hydrogen chloride ether solution was added, and the precipitated salt was filtered and recrystallized using ethanol to obtain the desired hydrochloride. The melting point of this product was 191 to 192 ° C.

Similarly, the following compounds were prepared from the corresponding appropriate starting materials.

(A) 1- [2- (diphenylmethoxy) ethyl] -4
-(1-Oxo-2-propenyl) piperazine hydrochloride; melting point 189-190 ° C.

(B) 1- [2- (diphenylmethoxy) ethyl] -4
-(1-Oxobutyl) piperazine hydrochloride;
Melting point: 192-193 ° C.

(C) 1- [2- (diphenylmethoxy) ethyl] -4
-(1-Oxopentyl) piperazine hydrochloride; Melting point: 180.5-181.5 ° C.

(D) 1- [2- (diphenylmethoxy) ethyl] -4
-(1-Oxohexyl) piperazine hydrochloride; Melting point: 187-190 ° C.

(F) 1- [2- [2- (4-fluorophenyl) methoxy] ethyl] -4- (1-oxohexyl) piperazine hydrochloride; melting point: 169-170 ° C.

The acid amide-type compound of general formula (I) could be reduced according to Example 4 to convert it to the appropriate compound of general formula (I).

(G) 1- [2- (diphenylmethoxy) ethyl] -4
-(N-hexyl) piperazine dihydrochloride; melting point: 216-217 ° C.

Elemental analysis: As C ₂₅ H ₃₆ N ₂ O (base): Calculated value (%); C 78.90; H 9.54; N 7.36; Experimental value (%); C 78.78; H 9.66; N 7.30. (H) 1- [2- (diphenylmethoxy) ethyl] -4
-(N-Pentyl) piperazine hydrochloride; melting point: 2
13-214 ° C.

Elemental analysis: As C ₂₄ H ₃₄ N ₂ O (base): Calculated value (%); C 78.64; H 9.35; N 4.37; Experimental value (%); C 78.60; H 9.48; N 4.39. (I) 1- [2- (diphenylmethoxy) ethyl] -4
-(N-Butyl) piperazine hydrochloride; melting point: 209
~ 211 ℃.

Elemental analysis: as C ₂₃ H ₃₂ N ₂ O (base): calculated value (%); C 78.36; H 9.15; N 7.95; experimental value (%); C 78.17; H 9.20; N 7.84. (J) 1- [2- [Bis (4-fluorophenyl) methoxy] ethyl] -4- (n-propyl) piperazine dihydrochloride; The physical properties of this were similar to those shown in Example 7.

(K) 1- [2- (diphenylmethoxy) ethyl] -4
-(2-propenyl) piperazine dihydrochloride;
The physical properties of this were similar to those shown in Example 13.

Example 6 1- [2-[(4-hydroxyphenyl) -4- (4-
Preparation of fluorophenyl) methoxy] ethyl] -4-propylpiperazine di (hydrogen maleate) 1- [2-[(4-benzyloxyphenyl) -4-fluorophenyl) methoxy) ethyl] -4- in 140 ml of methanol A solution of 13.3 g of (2-propenyl) piperazine dihydrochloride was hydrogenated at atmospheric pressure in the presence of 6.0 g of 10% palladium on charcoal. After the reaction was complete, the catalyst was filtered off and the filtrate was evaporated under reduced pressure.

The residue was dissolved in water and the base was released by adding aqueous ammonium hydroxide solution, which was extracted into ether. The ether layer was then extracted with water, dried over anhydrous magnesium sulfate and the ether phase was treated with maleic acid ether solution. The resulting precipitate was filtered and dried to obtain the desired maleate salt. Melting point 129-1
It was 32 ° C.

Elemental analysis: As C ₂₂ H ₂₉ FN ₂ O ₂ (base): Calculated value (%); C 70.94; H 7.85; F 5.10; N 7.52; Experimental value (%); C 71.10; H 7.64; F 5.28; N 7.39. Example 7 Preparation of 1- [2- [bis (4-fluorophenyl) -methoxy] ethyl] -4-propylpiperazine hydrochloride 1- [2- [bis (4-fluorophenyl) -methoxy] ethyl] 2 g piperazine, 0.35 propionaldehyde
g, and sodium cyanoborohydride 0.4 g
The mixture liquid dissolved in 28 ml of the solution was stirred at room temperature for 4 hours, and then 35 ml of 0.4N hydrochloric acid solution was added thereto, and the mixture liquid was
The mixture was stirred at room temperature for another hour.

After evaporating methanol under reduced pressure, an aqueous sodium hydroxide solution was added to the residue to alkalize it. After extraction with benzene, the benzene layer was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.

The obtained residue was taken up with absolute ethanol, and then a hydrogen chloride ether solution was added to obtain the desired product.
The melting point was 199-200 ° C.

Elemental analysis: As C ₂₂ H ₂₈ F ₂ N ₂ O (base): Calculated value (%); C 70.56; H 7.54; F 10.5; N 7.48; Experimental value (%); C 70.67; H 7.48; F 10.19; N 7.67. Example 8 1- [2- [1-bis (4-fluorophenyl) -ethoxy] ethyl] -4- (2-propenyl) piperazine
Preparation of dihydrochloride 4.6 g of 4'-fluoroacetophenone was dissolved in 10 ml of tetrahydrofuran, and 20.0 ml of tetrahydrofuran solution of 1.5M 4-fluorophenylmagnesium bromide was dissolved in this solution.
Was added dropwise.

The mixture was refluxed for 1 hour, cooled to room temperature, and added to 45 ml of anhydrous xylene, 1- (2-chloroethyl) -4- (2.
A solution of 5.7 g of -propenyl) piperazine was added to this and the mixture was boiled for 3 hours. Next, pour this mixture into water, separate the organic layer, and remove the aqueous phase.
Extracted twice with 25 ml xylene.

An ammonium hydroxide solution was added to this aqueous acidic solution to make it alkaline, and then extraction was performed with ether. The extracted ether phases were combined, dried over anhydrous magnesium sulphate and evaporated further.

The resulting residue was mixed with a chloroform / methanol mixture (98:
Chromatography was performed using a Kieselgel column with 2) as the eluent. Combine the appropriate fractions together,
Evaporation was performed under reduced pressure, and a hydrogen chloride ether solution was further added to precipitate dihydrochloride. The obtained crystals were separated by filtration and dried to obtain the target compound. Melting point is 187-189.5 ° C
Met.

Elemental analysis: C ₂₃ H ₂₈ F ₂ N ₂ O (base): Calculated value (%); C 71.47; H 7.30; F 9.83; N 7.25; Experimental value (%); C 71.60; H 7.37; F 9.75; N 7.30. Example 9 Preparation of 1- [2- [bis (4-chlorophenyl) methoxy] ethyl] -4- (2-propenyl) piperazine dihydrochloride 4- (2-hydroxyethyl) -1- (2-propenyl ) A solution of 8.5 g of piperazine in 30 ml of ethanol was reacted with 2.7 g of sodium methoxide, and then methanol was distilled off from the reaction mixture. Toluene in the residue 1
After adding 00 ml, the mixture was azeotropically distilled to completely remove the methanol component (about 20 ml of toluene was also distilled off).

To this residue, 4,4'-dichlorobenzhydryl chloride 1
A solution of 4.1 g dissolved in 30 ml of anhydrous toluene was added dropwise, and the mixture was boiled under reflux for 4 hours. The organic phase was then separated, washed with water, dried over anhydrous magnesium sulphate and evaporated under reduced pressure.

The obtained residue was taken up in anhydrous ether, hydrogen chloride ether solution was added, and the resulting precipitate was filtered and recrystallized using a methanol / ether mixture to obtain the desired dihydrochloride. The melting point was 218.5-220 ° C.

Elemental analysis: as C ₂₂ H ₂₆ Cl ₂ N ₂ O (base): calculated (%); C 65.18; H 6.47; Cl 17.49; N 6.91; experimental (%); C 65.31; H 6.52; Cl 17.29; N 6.83. Example 10 Preparation of 1- [2-[(4-fluorophenyl) -phenylmethoxy] ethyl] -4-propylpiperazine dihydrochloride 11.0 g of 4-fluorobenzhydrochloride, and 1-
(2-hydroxyethyl) -4-propylpiperazine 1
The mixture containing 7.2 g was heated at a temperature of 150 to 170 ° C. under a nitrogen atmosphere for 30 times.
Heated for minutes. The mixture was then cooled to 90-100 ° C and water was added. After further cooling to room temperature, the mixture was extracted with benzene, the organic layer was washed with water until it became neutral, dried with anhydrous magnesium sulfate, and evaporated.

The obtained residue was dissolved in absolute ethanol, and then a hydrogen chloride ether solution was added to form dihydrochloride. The mixture was diluted with ether, and the precipitated crystalline dihydrochloride was filtered, washed with ether and dried to obtain the target compound. The melting point was 194-195 ° C.

Elemental analysis: As C ₂₂ H ₂₉ FN ₂ O (base): Calculated value (%); C 74.12; H 8.20; F 5.33: N 7.86; Experimental value (%); C 74.30; H 8.33; F 5.41; N 7.89 The following compounds (provided that R ₅ is a hydrogen atom, n is 2 and R ₆ is a 2-propenyl group) are treated in the same manner as in Example 9 or 10 above using an appropriate starting material.

Example 11 Preparation of 1- [2-[(4-chlorophenyl)-(4-fluorophenyl) methoxy] ethyl] -4-propylpiperazine dihydrochloride 1- [2-[(4-chlorophenyl)-(4-fluoro) (Phenyl) methoxy] acetyl] -4-propylpiperazine (8.1 g) was dissolved in 100 ml of ether and added dropwise to 30 ml of 1.0M lithium aluminum hydride ether solution while stirring under a nitrogen gas atmosphere, and then the mixture was refluxed for 3 hours. Let Next, this mixture was cooled to 0 ° C., and an aqueous solution of sodium potassium tartrate was added to decompose it.

The aqueous phase is extracted with ether, the extracted ether solutions are combined, washed with saturated aqueous sodium chloride solution,
It was further dried over anhydrous magnesium sulfate and then evaporated. A hydrogen chloride ether solution was added to an ethanol solution of the obtained residue to adjust the pH to 2.5 to 3. As a result, the precipitated crystals were separated by filtration and dried to obtain the desired dihydrochloride. The melting point was 195-197 ° C.

Elemental analysis: C ₂₂ H ₂₈ ClFN ₂ O (base): Calculated value (%); C 67.59; H 7.22; Cl 9.07; F 4.86; N 7.17; Experimental value (%); C 67.71; H 7.40; Cl 9.18 ; F 4.82; N 7.30. Example 12 (a) 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4- (2-methyl-2-propenyl)
Preparation of piperazine dihydrochloride 1- [2- [bis (4-fluorophenyl) methoxy]
Ethyl] piperazine 6.6 g, anhydrous potassium carbonate powder 3.0 g, 3
A mixture containing 2.0 g of -chloro-2-methylpropene and 70 ml of anhydrous acetone was refluxed under stirring for 6 hours. Next, acetone was distilled off under reduced pressure, the residue was taken up in water, and further extracted with benzene. The organic phase was washed with water, dried over anhydrous potassium carbonate and evaporated under reduced pressure.
The residue was purified by chromatography using Kiesel column with chloroform as the eluent.

After evaporation of appropriate fractions, a hydrogen chloride ether solution was added to precipitate the desired dihydrochloride. The melting point was 197-199 ° C.

Further, a dilute aqueous solution of ammonium hydroxide was added to release the base from the dihydrochloride.

Elemental analysis: C ₂₃ H ₂₈ F ₂ N ₂ O (base): Calculated value (%); C 71.48; H 7.30; F 9.83; N 7.25; Experimental value (%); C 71.60; H 7.35; F 9.74; N 7.33. The following compounds were prepared by treating in the same manner as in the above example.

(B) 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4- (n-butyl) piperazine dihydrochloride; melting point: 219-220 ° C.

Elemental analysis: as C ₂₃ H ₃₆ F ₂ N ₂ O (base): Calculated value (%); C 71.10; H 7.78; F 9.78; N 7.21; Experimental value (%); C 71.23; H 7.81; F 9.63; N 7.33. (C) 1- [2-[(4-chlororophenyl) -4-
(4-Fluorophenyl) methoxy] ethyl] -4-
(N-Butyl) piperazine dihydrochloride; melting point: 2
20 ~ 221 ℃.

Elemental analysis: As C ₂₃ H ₃₀ ClFN ₂ O (base): Calculated value (%); C 68.21; H 7.47; Cl 8.76; F 4.69; N 6.92; Experimental value (%); C 68.00; H 7.41; Cl 8.53 ; F 4.81; N 7.03. (D) 1- [2-[(3,4-dichlororophenyl) phenylmethoxy] ethyl] -4- (n-butyl) piperazine dihydrochloride; Melting point: 221-22.5 ° C.

Elemental analysis: as C ₂₃ H ₃₀ Cl ₂ N ₂ O (base): calculated (%); C 65.55; H 7.18; Cl 16.83; N 6.65; experimental (%); C 65.73; H 7.24; Cl 16.66; N 6.79. Example 13 1- [2-[(diphenylmethoxy) ethyl] -4-
Preparation of (2-propenyl)) piperazine dihydrochloride 1- [2-[(diphenylmethoxy) ethyl] -4- (2-propynyl)) piperazine 1 in 170 ml of methanol
6.7 g, zinc acetate dihydrate 0.4 g, and piperazine 10
The solution containing 1 ml was laminated with a catalyst under atmospheric pressure.
Hydrogenated in the presence of 3.0 g. After absorbing a calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated under reduced pressure.

As a result, the residue obtained was taken up with benzene, washed with water, dried over anhydrous magnesium sulphate and then evaporated. The obtained residue was purified by Kieselgel column chromatography using a chloroform / methanol (98: 2) mixture as an eluent. Further, a hydrogen chloride ether solution was added to obtain the desired dihydrochloride from an appropriate fraction. The melting point was 204-206 ° C.

Elemental analysis: As C ₂₂ H ₂₈ N ₂ O (base): Calculated value (%); C 78.53; H 8.39; N 8.33; Experimental value (%); C 78.67; H 8.29; N 8.35. Example 14 1- [2- [bis (4-fluorophenyl) methoxy]
Preparation of ethyl] -4- (2-propynyl)) piperazine dihydrochloride 1- [2- [bis (4-fluorophenyl) methoxy]
Ethyl] piperazine 33.2 g, anhydrous potassium carbonate powder 15.5 g,
A mixture of 13.1 g of a 30% propargyl bromide toluene solution and 330 ml of anhydrous acetone was stirred at room temperature for 1 hour. Then it was evaporated under reduced pressure, the residue obtained was taken up with water and extracted with benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

The resulting residue was purified by chromatography using a Kiesel column using chloroform as the eluent. The target dihydrochloride was precipitated by adding a hydrogen chloride ether solution to an ether solution of this base. The melting point was 187-188 ° C.

Elemental analysis: As C ₂₂ H ₂₄ F ₂ N ₂ O (base): Calculated value (%); C 71.33; H 6.53; F 10.26; N 7.56; Experimental value (%); C 71.41; H 6.47; F 10.12; N 7.58. The following compounds were prepared from the appropriate starting materials in a similar manner to the above example.

(A) 1- [2-diphenylmethoxy) ethyl] -4-
(2-propynyl) piperazine dihydrochloride; melting point: 205-206 ° C.

Elemental analysis: As C ₂₂ H ₂₆ N ₂ O (base): Calculated value (%); C 79.00; H 7.84; N 8.38; Experimental value (%); C 79.20; H 7.78; F 8.19. (B) 1- [2-[(4-trifluoromethylphenyl)-(4-fluorophenyl) methoxy] ethyl]-
4- (propynyl) piperazine (oil substance); Elemental analysis: as C ₂₃ H ₂₄ F ₄ N ₂ O (base): calculated value (%); C 65.70; H 5.75; F 18.08; N 6.66; experimental value (%) ); C 65.86; H 5.76; F 18.20; N 6.51. Example 15 1- [2-[(4-trifluoromethylphenyl)-
(4-Fluorophenyl) methoxy] ethyl] -4-
Preparation of (n-propyl) piperazine dihydrochloride 1- [2-[(4-trifluoromethylphenyl)-
(4-Fluorophenyl) methoxy] ethyl] -4-
4.2 g of (2-propyl) piperazine was dissolved in 45 ml of methanol, and this was hydrogenated in the presence of 0.4 g of charcol supporting 10% palladium and at atmospheric pressure. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off and the filtrate was evaporated.

The obtained residue is dissolved in benzene, the organic layer is washed with water,
It was dried over anhydrous sodium sulphate and then evaporated. Dissolve the obtained residue in ethanol and add hydrogen chloride ethanol.
Add until pH reached 2.5-3. The precipitated crystalline substance was filtered off and recrystallized using methanol to obtain the desired dihydrochloride. The melting point was 212-214 ° C.

Elemental analysis: as C ₂₃ H ₂₈ F ₄ N ₂ O (base): calculated value (%); C 65.08; H 6.65; F 17.90; N 6.60; experimental value (%); C 65.10; H 6.69; F 17.81; N 6.63. Example 16 1- [2-[(4-fluorophenyl) -phenylmethoxy] ethyl] -4- (2-propenyl) piperazine
Preparation of dihydrochloride 4-toluenesulfonic acid monohydrate (12.0 g) and 1- (2-hydroxyethyl) -4- (2-propenyl) piperazine (5.1 g) in dimethylformamide (45 ml) were dissolved in toluene (150 ml) and 4-fluorobenzidine. 7.9 g of hydrol was added to the dissolved solution and then the mixture was boiled to azeotropically remove the water formed in the condensation reaction. After completion of the reaction (controlled by thin layer chromatography), the mixture was cooled and extracted with water.

The aqueous phase was made alkaline by the addition of a concentrated aqueous solution of ammonium hydroxide and then extracted with benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate,
It was then filtered through a layer of 50 g of aluminum oxide and then evaporated.

An anhydrous ether solution of the obtained residue was adjusted to pH 2.5 to 3 by adding hydrogen chloride ether solution. As a result, the resulting precipitate was filtered and recrystallized with methanol to obtain the desired dihydrochloride. The melting point was 191-192 ° C.

Elemental analysis: As C ₂₂ H ₂₇ FN ₂ O (base): Calculated value (%); C 74.55; H 7.68; F 5.36; N 7.90; Experimental value (%); C 74.41; H 7.73; F 5.41; N 7.88 Example 17 The compound of the present invention was treated as follows and formulated into a pharmaceutical composition.

Preparation of tablets Active ingredient 50g, lactose 92g, potato starch 40g, polyvinylpyrrolidone 4g, talc 6g, magnesium stearate 1g, colloidal silicon dioxide (Aerosil), and ultra amylopectin 6g are mixed and granulated in a wet state, It was then compressed into tablets.

1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4-, where the weight of each tablet was 200 mg
It contained 50 mg of the active ingredient consisting of (2-propenyl) piperazine dihydrochloride.

Production of sugar-coated tablets The tablets obtained as described above were covered with a coating layer consisting of sugar and talc. The dragees were then glazed with a mixture of beeswax and kanaba wax.

The weight of each sugar-coated tablet was 250 mg.

Preparation of Suspension A 100 ml suspension having the following composition was prepared.

Active ingredient Weight (g) Sodium hydroxide 0.26g Citric acid 0.30g Nipagin (methyl 4-hydroxybenzoate) 0.10g (Nipagin) Carbopol 940 (polyacrylic acid) 0.37g (Carbopol) Ethanol (96%) 1.00g Strawberry flavor 0.60 g Sorbitol (70 aqueous solution) 71.00 g Distilled water for injection (enough amount to make 100 ml in total) Carbopol 940 is nipagin and citric acid distilled water 2
To the solution in 0 ml was added in small portions under vigorous stirring. Then, after allowing this solution to stand for 10 to 12 hours, a solution prepared by dissolving the above sodium hydroxide in 1 ml of distilled water was added,
Further, sorbitol was mixed in, and finally an ethanol solution of the strawberry flavor was added with stirring.

The active ingredient was added little by little to the excipient and then the mixture was converted to a suspension using a dipped homogenizer. Finally, the suspension was adjusted to 100 ml with distilled water and the suspension syrup obtained was passed through a colloid mill. The active ingredient is 1- [2- [bis (4-
Fluorophenyl) methoxy] ethyl] -4- (2-propenyl) piperazine.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Josef Terrej Budapest Hungary 1137 Katnaye Uzza 41 (72) Inventor Eva Palossii Budapest Hungary 1025 Bend Utzua 21 (72) Inventor Haidu Budapest 1205 Tat Hungary La Terre Be / 4 (72) Inventor Laszlo Sporny Budapest Hungary 1114 Savor Chuka Em Uzza 7 (72) Inventor Dora Grosau Hungary Budapest 1021 Napla Volgo Uzza 17 (72) Inventor Erjebet Lapish Hungary Budapest 1172 Avari Aza 86 (72) Inventor Istvan Raslovski Hungary Country Budapest 1111 Baltok Berah Uzza 16 (56) References JP-A-50-142574 (JP, A) JP-A-53-82789 (JP, A) JP-B-35-14225 (JP-B1) JP-B Sho 36-427 (JP, B1) Neuropharmacology Vol. 24, No. 12, p. 1171-1174 (1985)

Claims (21)

[Claims] 1. A 1,4-disubstituted piperazine derivative represented by the following general formula, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof. (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other and represent a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group and phenyl. C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3. ) 2. The compound of the general formula (I) is 1- [2-
[Bis (4-fluorophenyl) methoxy] ethyl]-
The 1,4-disubstituted piperazine derivative, the acid addition salt and the quaternary ammonium salt according to claim 1, which is 4- (2-propenyl) -piperazine. 3. The compound of the general formula (I) is 1- [2-
[(3,4-Dichlorophenyl) -phenylmethoxy] ethyl] -4- (2-propenyl) -piperazine 1,4-disubstituted piperazine derivative and acid addition salt according to claim (1). And quaternary ammonium salts. 4. The compound of general formula (I) is 1- [2-
[Bis (4-fluorophenyl) methoxy] ethyl]-
A 1,4-disubstituted piperazine derivative according to claim 1, which is 4- (2-propynyl) piperazine.
Acid addition salts and quaternary ammonium salts. 5. A 1,4-disubstituted piperazine derivative having the following general formula, as well as its pharmacologically usable acid addition salts and quaternary ammonium salts. (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other and represent a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group and phenyl. A C _1-4 alkyloxy group or 1 (2
-Propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl group, n is an integer of 2 or 3, which is an effective pharmaceutical composition for treating a disease by reducing the function of dopamine system. 6. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3, and is a compound of the following general formula (II): [In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as above, and Y is
An OM group (where M is an alkali metal or MgHlg (where Hlg is halogen)] or a hydroxyl group] is a compound of the following general formula (III): (In the formula, R ₆ and n are the same as above, X is a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group when Y is an OM group, and a halogen, a hydroxyl group, an alkylsulfonyl group when Y is a hydroxyl group. Oxy group or arylsulfonyloxy group), and if desired, the compound thus obtained is converted into an acid addition salt with an organic acid or an inorganic acid, or converted into a quaternary ammonium salt with a quaternizing agent. Or, if desired, the acid addition salt or quaternary ammonium salt is converted to the corresponding free base, or if desired, the free base is converted to the acid addition salt or quaternary ammonium salt. And a manufacturing method. 7. The method according to claim 6, which is carried out in a solvent inert to the reaction. 8. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3], wherein the compound of the following general formula (IV): (Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are the same as above and Hlg is halogen), and a piperazine derivative of the following general formula (V): [Wherein R ₆ and n are the same as above, X is a hydroxyl group or an OM ′ group (wherein M ′ is an alkali metal)], and if desired, the compound thus obtained is treated with an organic acid or Whether converted to an acid addition salt with an inorganic acid, or a quaternary ammonium salt with a quaternizing agent, and if desired, the acid addition salt or quaternary ammonium salt is converted to the corresponding free base. Further, if desired, the free base is converted into an acid addition salt or a quaternary ammonium salt thereof, which is a production method. 9. The method according to claim (8), which is carried out in a solvent inert to the reaction. 10. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3], wherein the compound of the following general formula (VI): (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as those described above for Z.
Is a halogen, an alkylsulfonyloxy group or an arylsulfonyloxy group), and a piperazine derivative represented by the following general formula (VII): (Wherein R ₆ is the same as described above), and if desired, the compound thus obtained is converted into an acid addition salt with an organic acid or an inorganic acid, or a quaternary ammonium salt is added with a quaternizing agent. A salt or, if desired, the acid addition salt or quaternary ammonium salt is converted to the corresponding free base, or optionally the free base is converted to its acid addition salt or quaternary ammonium salt. A manufacturing method characterized by: 11. The production method according to claim 10, which is carried out in a solvent inert to the reaction. 12. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3], wherein the compound of the following general formula (VIII): (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as described above) is a compound of the following general formula (IX): ZR ₆ (IX) (wherein Z is halogen , An alkylsulfonyloxy group, or an arylsulfonyloxy group, and R ₆ are the same as those described above), and if desired, the compound thus obtained is converted to an acid addition salt with an organic acid or an inorganic acid, or Converting to a quaternary ammonium salt with a quaternizing agent, and if desired, converting the acid addition salt or quaternary ammonium salt to the corresponding free base, and further optionally converting the free base to the acid addition salt. Alternatively, a production method comprising converting into a quaternary ammonium salt. 13. The production method according to claim 12, which is carried out in a solvent inert to the reaction. 14. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. group, n is a manufacturing method of a 2 or 3 of an integer], the compound of general formula (I) _{(where, R 1, R 2, R} 3, R 4, R 5 and n are the same as defined above, R ₆ Is partially or completely reduced from a C _3-6 alkynyl group to give a compound of general formula (I) (wherein R ₆ is C
_{3 to 6} alkenyl group or alkynyl group, R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ and n are the same as the above), and if desired, the compound thus obtained is converted into an acid addition salt with an organic acid or an inorganic acid, or a quaternary ammonium salt is added with a quaternizing agent. A salt or, if desired, the acid addition salt or quaternary ammonium salt is converted to the corresponding free base, or optionally the free base is converted to its acid addition salt or quaternary ammonium salt. A manufacturing method characterized by: 15. The production method according to claim 14, which is carried out in a solvent inert to the reaction. 16. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3], wherein the compound of the general formula (I) (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as defined above) ₆ is a compound of formula (I) (wherein R ₆ is C _3-6 ) by partially reducing the C _3-6 alkynyl group.
Alkenyl groups R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as above), and if desired, the compound thus obtained is converted into an acid addition salt with an organic acid or an inorganic acid. Or a quaternizing agent to convert it to a quaternary ammonium salt, and if desired, to convert this acid addition salt or quaternary ammonium salt to the corresponding free base, and, if desired, to convert the free base to A production method comprising converting the acid addition salt or a quaternary ammonium salt. 17. The method according to claim 16, which is carried out in a solvent inert to the reaction. 18. The method according to claim 16, wherein the reduction reaction is carried out by a catalytic hydrogenation reaction. 19. The following general formula (I): A 1,4-disubstituted piperazine derivative consisting of, and a pharmacologically usable acid addition salt and quaternary ammonium salt thereof, wherein R ₁ , R ₂ , R ₃ and R ₄ are the same or different from each other. And different from each other, a hydrogen atom, a halogen, a trihalomethyl group, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a phenyl C _1-4 alkyloxy group or 1-
Selected from a (2-propenyl-4-piperazinyl) group, R ₅ is a hydrogen atom or a C _1-4 alkyl group, R ₆ is a C _3-6 alkenyl group, or a C _3-6 alkynyl. Group, n is an integer of 2 or 3], wherein the acid amide of the following general formula (X): (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n are the same as those described above for R ₆
Is a C _3-6 alkenyl group or a C _3-6 alkynyl group) and, if desired, the compound thus obtained is converted into an acid addition salt with an organic acid or an inorganic acid, or Converting to a quaternary ammonium salt with a quaternizing agent, and if desired, converting the acid addition salt or quaternary ammonium salt to the corresponding free base, and further optionally converting the free base to the acid addition salt. Alternatively, a production method comprising converting into a quaternary ammonium salt. 20. The production method according to claim (19), which is carried out in a solvent inert to the reaction. 21. The method according to claim 19, wherein the reduction reaction is carried out using an aluminum complex.